Basal cell carcinoma (BCC) is the most commonly diagnosed cancer in North America. Although BCCs are generally regarded as follicular tumors, the cells of origin for this cancer-and even whether these cells originate from the hair follicle-remain a subject of debate. Stem cells are attractive candidates as potential progenitor cells for cancer, given their long-lived nature and self renewal ability;however, in the skin, discrete stem cell populations reside in several compartments, including the follicular bulge, sebaceous glands, interfollicular epidermis, and the junctional zone, a recently identified domain of the upper hair follicle. Potentially, cells from any of these compartments can give rise to BCC. In humans, BCCs commonly display upregulated Hedgehog (Hh) signaling, and skin-specific expression of Hh pathway components such as Smoothened and Gli2 can induce the formation of BCC-like lesions in mice. Using a variety of in vivo approaches, this study seeks to identify and characterize the cells of origin for tumors arising from two Hh- dependent mouse models of BCC. In doing so, long-standing questions regarding the pathogenesis of this disease will be addressed, including, (1) Can different cell types give rise to BCCs depending on the oncogenic initiating event? (2) Can cells from the interfollicular epidermis generate BCCs independently of the hair follicle? (3) Can cells from the follicular bulge give rise to BCC? And (4), Can specific keratinocyte subpopulations with differing tumorigenic competency be isolated? The findings from this proposal will hopefully shed light on the pathogenesis of BCC, as well as on the behaviors of the various cell types that comprise the skin and hair follicle.